The proposed research plan will explore the molecular mechanisms involved in the chemotherapy-induced apoptotic/antiapoptotic response mechanisms that are regulated by NF-kappaB. The training that Dr. Cusack will receive under the direct supervision of Dr. Albert Baldwin during the award period will establish a foundation in basic science methodology critical to the success of an independent investigator. Dr. Cusack's long- term career goals are to become an academic surgical oncologist who can combine multidisciplinary cancer patient care with a study of the tumor biology of his patients' disease. His ultimate goal is to develop novel treatment strategies that improve the response to anti-cancer therapies. Funding of the requested award would ensure the protected time away from clinical responsibilities, necessary to participate in both the courses and bench work needed to become trained in tumor biology. Support for this proposal comes from the UNC Lineberger Comprehensive Cancer Center and the Department of Surgery. Dr. Cusack is provided space in Dr. Baldwin's laboratory as well as use of the core facilities of the Cancer Center. This support currently provides equipment, reagents, and consumables for the laboratory and protected time away from clinical responsibilities. Funding of this proposal will ensure that 75 percent of Dr. Cusack's time will be devoted to the proposed research. Our preliminary studies indicate that (1) NF-kappaB activation is induced by chemotherapy (CPT-11); (2) both a modified form of the natural inhibitor of NF-kappaB and a proteasome inhibitor block chemotherapy-induced activation of NF-kappaB; and (3) inhibition of NF-kappaB activation can markedly enhance the apoptotic response to chemotherapy in cancer cells both in vitro and in vivo. The mechanism by which chemotherapy induces the activation of NF-kappaB and the mechanism by which NF-kappaB inhibits apoptosis are not known. In this proposal, we have proposed a set of experiments that will evaluate how NF-kappaB activation is induced by chemotherapy, and how NF-kappaB inhibits the apoptotic response to chemotherapy. Also, we will analyze novel inhibition of NF-kappaB for their potential as adjuvants in cancer therapy. These studies will contribute to a better understanding of the underlying mechanisms involved in the NF-kappaB-mediated antiapoptotic response that is induced by chemotherapy, and ultimately to the development of new approaches that will improve cancer chemotherapy.